Decreased Prevalence of Alzheimer Disease Associated With 3-Hydroxy-3-Methyglutaryl Coenzyme A Reductase Inhibitors

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Abstract
THE PATHOPHYSIOLOGY of Alzheimer disease (AD) has many connections with cholesterol metabolism. Epidemiological studies show that patients with elevated cholesterol levels have an increased risk of AD.1,2 One of the major risk factors for AD, is apolipoprotein E type 4 (APOE4), which is a cholesterol transport protein.3,4 Patients carrying the APOE4 polymorphism have elevated cholesterol levels, although at least part of the risk for AD seems to derive from factors unrelated to cholesterol level.2 Patients with the APOE4 polymorphism also have increased risk of cardiovascular disease, and epidemiological studies show that patients with cardiovascular disease have an increased risk of AD.5 A second putative risk factor for AD, α2-macroglobulin, binds to the same receptor as does APOE4.6 This receptor, the lipoprotein receptor–related protein, is important for cellular uptake of cholesterol.7 Cholesterol also effects the biology of β-amyloid (Aβ). β-αmyloid is a protein that accumulates in the affected brains of patients with AD and is thought to cause the neurodegeneration underlying AD.8 Production of the Aβ peptide is increased by cholesterol in some cells.9 These multiple links suggest a potentially important relation between cholesterol and AD.